{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T03:29:43Z","timestamp":1777087783447,"version":"3.51.4"},"reference-count":36,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,1,26]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adoptive cell therapy using cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has demonstrated efficacy posttransplant. Despite the predicted limited engraftment of CMV-CTLs derived from third-party donors, partially matched third-party donor\u2013derived CMV-CTLs have demonstrated similar response rates to those derived from primary hematopoietic cell transplantation donors. Little is known about the mechanisms through which adoptive cellular therapies mediate durable responses. We performed a retrospective analysis of patients receiving CMV-CTLs for treatment of CMV viremia and\/or disease after allogeneic transplant between September of 2009 and January of 2018. We evaluated whether response to adoptively transferred CMV-CTLs correlated with immune reconstitution (IR), using validated CD4+ IR milestones of 50 \u00d7 106\/L and 200 \u00d7 106\/L. In this analysis, a cohort of 104 patients received CMV-CTLs derived from a primary transplant donor (n = 25), a third-party donor (n = 76), or both (n = 3). Response to therapy did not increase the likelihood of achieving CD4+ IR milestones at 1 (P = .53 and P &amp;gt; .99) or 2 months (P = .12 and P = .33). The origin of CMV-CTLs did not impact subsequent CD4+\u00a0IR. CMV-CTLs appeared to interact with host immunity in mediating responses. Recipients with a baseline CD4 &amp;gt;50 \u00d7 106\/L had higher response to therapy (P = .02), improved overall survival (P &amp;lt; .001), and protection from CMV-related death (P = .002). Baseline endogenous immunity appears to improve CMV-related and overall survival in this cohort and can be an important marker at the initiation of therapy.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002735","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T21:24:03Z","timestamp":1611437043000},"page":"496-503","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":36,"title":["Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses"],"prefix":"10.1182","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8405-1141","authenticated-orcid":false,"given":"Vanessa A.","family":"Fabrizio","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;"},{"name":"Department of Pediatrics, Weill Cornell Medical College, New York, NY; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Irene","family":"Rodriguez-Sanchez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3236-6093","authenticated-orcid":false,"given":"Audrey","family":"Mauguen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0794-3226","authenticated-orcid":false,"given":"Parastoo B.","family":"Dahi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina","family":"Doubrovina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;"},{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"O\u2019Reilly","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4175-5728","authenticated-orcid":false,"given":"Susan E.","family":"Prockop","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;"},{"name":"Department of Pediatrics, Weill Cornell Medical College, New York, NY; and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","published-online":{"date-parts":[[2021,1,22]]},"reference":[{"issue":"3","key":"2021012216350101200_B1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1056\/NEJM199501193320303","article-title":"Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy","volume":"332","author":"Mackall","year":"1995","journal-title":"N Engl J Med"},{"issue":"4","key":"2021012216350101200_B2","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1172\/JCI200522492","article-title":"Age-dependent incidence, time course, and consequences of thymic renewal in adults","volume":"115","author":"Hakim","year":"2005","journal-title":"J Clin Invest"},{"issue":"8","key":"2021012216350101200_B3","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1080\/21505594.2016.1208866","article-title":"Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection","volume":"7","author":"Mehta","year":"2016","journal-title":"Virulence"},{"issue":"1","key":"2021012216350101200_B4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1634\/stemcells.18-1-10","article-title":"T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review","volume":"18","author":"Mackall","year":"2000","journal-title":"Stem Cells"},{"issue":"2","key":"2021012216350101200_B5","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1182\/blood.V93.2.467","article-title":"Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions","volume":"93","author":"Small","year":"1999","journal-title":"Blood"},{"issue":"3","key":"2021012216350101200_B6","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1046\/j.1365-2141.2001.03135.x","article-title":"Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients","volume":"115","author":"Maury","year":"2001","journal-title":"Br J Haematol"},{"issue":"2","key":"2021012216350101200_B7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.1365-2141.2004.04891.x","article-title":"Clinical impact of early absolute lymphocyte count after allogeneic stem cell transplantation","volume":"125","author":"Kim","year":"2004","journal-title":"Br J Haematol"},{"issue":"5","key":"2021012216350101200_B8","doi-asserted-by":"crossref","first-page":"e194","DOI":"10.1016\/S2352-3026(15)00045-9","article-title":"Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis","volume":"2","author":"Admiraal","year":"2015","journal-title":"Lancet Haematol"},{"issue":"6","key":"2021012216350101200_B9","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1016\/j.jaci.2016.12.992","article-title":"Viral reactivations and associated outcomes in the context of immune reconstitution after pediatric hematopoietic cell transplantation","volume":"140","author":"Admiraal","year":"2017","journal-title":"J Allergy Clin Immunol"},{"issue":"9","key":"2021012216350101200_B10","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.jcyt.2020.05.005","article-title":"Early CD4+ T cell reconstitution as predictor of outcomes after allogeneic hematopoietic cell transplantation","volume":"22","author":"van Roessel","year":"2020","journal-title":"Cytotherapy"},{"key":"2021012216350101200_B11","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1182\/asheducation-2015.1.215","article-title":"Immune reconstitution following stem cell transplantation","volume":"2015","author":"van den Brink","year":"2015","journal-title":"Hematology Am Soc Hematol Educ Program"},{"issue":"1","key":"2021012216350101200_B12","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.1016\/j.bbmt.2012.09.016","article-title":"Enhancing immune reconstitution: from bench to bedside","volume":"19","author":"van Den Brink","year":"2013","journal-title":"Biol Blood Marrow Transplant"},{"issue":"23","key":"2021012216350101200_B13","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1182\/blood-2016-06-724005","article-title":"Strategies before, during, and after hematopoietic cell transplantation to improve T-cell immune reconstitution","volume":"128","author":"de Koning","year":"2016","journal-title":"Blood"},{"issue":"11","key":"2021012216350101200_B14","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1038\/mt.2013.151","article-title":"Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant","volume":"21","author":"Gerdemann","year":"2013","journal-title":"Mol Ther"},{"issue":"242","key":"2021012216350101200_B15","doi-asserted-by":"crossref","first-page":"242ra83","DOI":"10.1126\/scitranslmed.3008825","article-title":"Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT","volume":"6","author":"Papadopoulou","year":"2014","journal-title":"Sci Transl Med"},{"key":"2021012216350101200_B16","doi-asserted-by":"crossref","first-page":"CT107","DOI":"10.1158\/1538-7445.AM2015-CT107","article-title":"Abstract CT107: Epstein-Barr virus-specific cytotoxic T lymphocytes for treatment of rituximab-refractory Epstein-Barr virus-associated lymphoproliferative disorder","volume":"75","author":"Prockop","year":"2015","journal-title":"Cancer Res"},{"issue":"21","key":"2021012216350101200_B17","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1182\/blood.V124.21.184.184","article-title":"Third party donor derived CMV specific T cells for the treatment of refractory CMV viremia and disease after hematopoietic stem cell transplant","volume":"124","author":"Prockop","year":"2014","journal-title":"Blood"},{"issue":"26","key":"2021012216350101200_B18","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1182\/blood-2016-01-628982","article-title":"T cells for viral infections after allogeneic hematopoietic stem cell transplant","volume":"127","author":"Bollard","year":"2016","journal-title":"Blood"},{"issue":"5","key":"2021012216350101200_B19","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1182\/blood-2009-08-239186","article-title":"Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients","volume":"115","author":"Heslop","year":"2010","journal-title":"Blood"},{"issue":"9","key":"2021012216350101200_B20","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/bmt.2016.17","article-title":"Virus-specific T-cell banks for \u201coff the shelf\u201d adoptive therapy of refractory infections","volume":"51","author":"O\u2019Reilly","year":"2016","journal-title":"Bone Marrow Transplant"},{"issue":"9","key":"2021012216350101200_B21","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/j.bbmt.2015.05.015","article-title":"Immunotherapy with donor T cells sensitized with overlapping pentadecapeptides for treatment of persistent cytomegalovirus infection or viremia","volume":"21","author":"Koehne","year":"2015","journal-title":"Biol Blood Marrow Transplant"},{"issue":"20","key":"2021012216350101200_B22","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1182\/blood-2015-11-679639","article-title":"Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis","volume":"127","author":"Teira","year":"2016","journal-title":"Blood"},{"issue":"11","key":"2021012216350101200_B23","doi-asserted-by":"crossref","first-page":"3916","DOI":"10.1182\/blood.V99.11.3916","article-title":"Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy","volume":"99","author":"Einsele","year":"2002","journal-title":"Blood"},{"issue":"24","key":"2021012216350101200_B24","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1182\/bloodadvances.2017010223","article-title":"Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells","volume":"1","author":"Withers","year":"2017","journal-title":"Blood Adv"},{"issue":"19","key":"2021012216350101200_B25","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1182\/blood-2009-07-232454","article-title":"Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation","volume":"114","author":"Leen","year":"2009","journal-title":"Blood"},{"issue":"4","key":"2021012216350101200_B26","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1093\/cid\/ciy549","article-title":"Autologous adoptive T-cell therapy for recurrent or drug-resistant cytomegalovirus complications in solid organ transplant recipients: a single-arm open-label phase I clinical trial","volume":"68","author":"Smith","year":"2019","journal-title":"Clin Infect Dis"},{"issue":"7","key":"2021012216350101200_B27","doi-asserted-by":"crossref","first-page":"e1149","DOI":"10.1002\/cti2.1149","article-title":"Mass cytometry reveals immune signatures associated with cytomegalovirus (CMV) control in recipients of allogeneic haemopoietic stem cell transplant and CMV-specific T cells","volume":"9","author":"McGuire","year":"2020","journal-title":"Clin Transl Immunology"},{"issue":"8","key":"2021012216350101200_B28","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1080\/21505594.2016.1221022","article-title":"CMV-specific immune reconstitution following allogeneic stem cell transplantation","volume":"7","author":"Blyth","year":"2016","journal-title":"Virulence"},{"issue":"11","key":"2021012216350101200_B29","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.bbmt.2020.07.024","article-title":"Low-level cytomegalovirus antigenemia promotes protective cytomegalovirus antigen-specific T cells after allogeneic hematopoietic cell transplantation","volume":"26","author":"Chen","year":"2020","journal-title":"Biol Blood Marrow Transplant"},{"issue":"18","key":"2021012216350101200_B30","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1182\/blood-2012-08-448977","article-title":"Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation","volume":"121","author":"Blyth","year":"2013","journal-title":"Blood"},{"issue":"2","key":"2021012216350101200_B31","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1182\/blood-2002-03-0993","article-title":"Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity","volume":"101","author":"Boeckh","year":"2003","journal-title":"Blood"},{"issue":"6","key":"2021012216350101200_B32","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.3109\/10428194.2014.963079","article-title":"Incidence, nature and mortality of cytomegalovirus infection after double-unit cord blood transplant","volume":"56","author":"Dahi","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"2021012216350101200_B33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jcv.2015.12.012","article-title":"In vitro studies of the impact of maribavir on CMV-specific cellular immune responses","volume":"75","author":"Stachel","year":"2016","journal-title":"J Clin Virol"},{"issue":"7","key":"2021012216350101200_B34","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.bbmt.2007.03.009","article-title":"Ganciclovir inhibits lymphocyte proliferation by impairing DNA synthesis","volume":"13","author":"Battiwalla","year":"2007","journal-title":"Biol Blood Marrow Transplant"},{"issue":"2","key":"2021012216350101200_B35","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1172\/JCI121127","article-title":"Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation","volume":"130","author":"Prockop","year":"2020","journal-title":"J Clin Invest"},{"key":"2021012216350101200_B36","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fcimb.2020.00202","article-title":"The CD4+ T cell response to human cytomegalovirus in healthy and immunocompromised people","volume":"10","author":"Lim","year":"2020","journal-title":"Front Cell Infect Microbiol"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/5\/2\/496\/1798455\/advancesadv2020002735.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/5\/2\/496\/1798455\/advancesadv2020002735.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T02:10:29Z","timestamp":1670897429000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/5\/2\/496\/474967\/Adoptive-therapy-with-CMV-specific-cytotoxic-T"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,22]]},"references-count":36,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,1,26]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2020002735","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,22]]}}}